Limited overlap between genetic effects on disease susceptibility and disease survival

Understanding disease progression is of high biological and clinical interest. Unlike disease susceptibility, whose genetic basis has been abundantly studied, less is known about the genetics of disease progression and its overlap with disease susceptibility. Considering nine common diseases (ncases ranging from 11,980 to 124,682) across seven biobanks, we systematically compared genetic architectures of susceptibility and progression, defined as disease-specific mortality. We identified only one locus substantially associated with disease-specific mortality and showed that, at a similar sample size, more genome-wide significant loci can be identified in a genome-wide association study of disease susceptibility. Variants substantially affecting disease susceptibility were weakly or not associated with disease-specific mortality. Moreover, susceptibility polygenic scores (PGSs) were weak predictors of disease-specific mortality, while a PGS for general lifespan was substantially associated with disease-specific mortality for seven of nine diseases. We explored alternative definitions of disease progression and found that genetic signals for macrovascular complications in type 2 diabetes overlap with similar phenotypes in the general population; however, these effects are attenuated. Overall, our findings indicate limited similarity in genetic effects between disease susceptibility and disease-specific mortality, suggesting that larger sample sizes, different measures of progression, or the integration of related phenotypes from the general population is needed to identify the genetic underpinnings of disease progression.